Exploration of Drug Science

Table 2. Comparative overview of AAV vectors, LNPs, and exosomes

Delivery platform	Delivery efficiency	Tissue specificity	Immunogenic risk	Advantages	Limitations
AAV vectors	Generally, high transduction efficiency	Specific serotypes exhibit tropism for muscle, liver, retina, etc.	Moderate to high; pre-existing neutralizing antibodies are common	Long-term gene expression; well-characterized biology	Limited transgene capacity (~ 4.7 kb); risk of immune response can reduce efficacy
Lipid nanoparticles (LNPs)	Moderate to high (depending on formulation)	Variable; targeting ligands can be incorporated for cell-type specificity	Relatively low, though some infusion-related reactions are possible	Non-viral, potentially allowing repeated dosing; scalable manufacturing	Potential instability in circulation; optimizing composition for each target remains complex
Exosomes	Variable and still under investigation	Intrinsic targeting properties reflect parent cell origin; some potential for tissue-specific engineering	Generally low; derived from endogenous vesicles, but risk varies by source	Natural biocompatibility; can carry diverse cargos (RNA, proteins, or small molecules)	Large-scale production and purification remain challenging; cargo loading and consistent characterization are still evolving fields

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AAV: adeno-associated virus

Supplementary materials

The supplementary table for this article is available at: https://www.explorationpub.com/uploads/Article/file/1008124_sup_1.pdf.

Declarations

Acknowledgments

The author is grateful to Sabine Weiskirchen (IFMPEGKC, RWTH Aachen University) for preparing the figures and graphical abstract for this article. During the preparation of this work, the author used the RWTHgpt to improve readability and language. After using the tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Author contributions

RW: Conceptualization, Funding acquisition, Writing—original draft, Writing—review & editing.

Conflicts of interest

Ralf Weiskirchen who is the Associate Editor of Exploration of Drug Science had no involvement in the decision-making or the review process of this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The study was supported by grants from the German Research Foundation [WE2554/17-1]; the Deutsche Krebshilfe [70115581]; and a grant from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University [PTD 1-5]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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References

Malech HL, Garabedian EK, Hsieh MM. Evolution of Gene Therapy, Historical Perspective. Hematol Oncol Clin North Am. 2022;36:627–45. [DOI] [PubMed] [PMC]

Hock RA, Miller AD, Osborne WR. Expression of human adenosine deaminase from various strong promoters after gene transfer into human hematopoietic cell lines. Blood. 1989;74:876–81. [PubMed]

Muul LM, Tuschong LM, Soenen SL, Jagadeesh GJ, Ramsey WJ, Long Z, et al. Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. Blood. 2003;101:2563–9. [DOI] [PubMed]

Jamalinia M, Weiskirchen R. Advances in personalized medicine: translating genomic insights into targeted therapies for cancer treatment. Ann Transl Med. 2025;13:18. [DOI] [PubMed] [PMC]

Khurana A, Sayed N, Singh V, Khurana I, Allawadhi P, Rawat PS, et al. A comprehensive overview of CRISPR/Cas 9 technology and application thereof in drug discovery. J Cell Biochem. 2022;123:1674–98. [DOI] [PubMed]

High KA, Roncarolo MG. Gene Therapy. N Engl J Med. 2019;381:455–64. [DOI] [PubMed]

Ormond KE, Mortlock DP, Scholes DT, Bombard Y, Brody LC, Faucett WA, et al. Human Germline Genome Editing. Am J Hum Genet. 2017;101:167–76. [DOI] [PubMed] [PMC]

Park SJ, Lee GE, Cho SM, Choi EH. Recent applications, future perspectives, and limitations of the CRISPR-Cas system. Mol Ther Nucleic Acids. 2025;36:102634. [DOI]

Hergenrother S, Husein M, Thompson C, Kalina E, Raina R. Updated Gene Therapy for Renal Inborn Errors of Metabolism. Genes (Basel). 2025;16:516. [DOI]

10.

He Q, Wang Y, Tan Z, Zhang X, Yu C, Jiang X. Mapping the therapeutic landscape of CRISPR-Cas9 for combating age-related diseases. Front Genome Ed. 2025;7:1558432. [DOI]

11.

Ingle RG, M Elossaily G, Ansari MN, Makhijani S. Unlocking the potential: advancements and applications of gene therapy in severe disorders. Ann Med. 2025;57:2516697. [DOI] [PubMed] [PMC]

12.

Allawadhi P, Singh V, Govindaraj K, Khurana I, Sarode LP, Navik U, et al. Biomedical applications of polysaccharide nanoparticles for chronic inflammatory disorders: Focus on rheumatoid arthritis, diabetes and organ fibrosis. Carbohydr Polym. 2022;281:118923. [DOI] [PubMed]

13.

Al Ayidh A, Abbas M, Parayangat M, Ijyas T. Advances in Nanomaterials for Targeted Drug Delivery: Emerging Trends and Future Prospects in Nanodrug Development. Curr Cancer Drug Targets. 2025;[Epub ahead of print]. [DOI] [PubMed]

14.

Nair DG, Weiskirchen R. Recent Advances in Liver Tissue Engineering as an Alternative and Complementary Approach for Liver Transplantation. Curr Issues Mol Biol. 2023;46:262–78. [DOI] [PubMed] [PMC]

15.

Song Z, Tao Y, Liu Y, Li J. Advances in delivery systems for CRISPR/Cas-mediated cancer treatment: a focus on viral vectors and extracellular vesicles. Front Immunol. 2024;15:1444437. [DOI] [PubMed] [PMC]

16.

Shah D, Gandhi S, Shah S, Patel K. Recent Breakthroughs in Exosome-Based Drug Delivery: A Comprehensive Review for Cancer Therapy. Cancer Biother Radiopharm. 2025;[Epub ahead of print]. [DOI] [PubMed]

17.

Yao T, Dong X, Wang X, Liu X, Fu L, Li L. Engineering exosomes for mRNA delivery: a review. Int J Biol Macromol. 2025;316:144662. [DOI] [PubMed]

18.

Molla G, Bitew M. Revolutionizing Personalized Medicine: Synergy with Multi-Omics Data Generation, Main Hurdles, and Future Perspectives. Biomedicines. 2024;12:2750. [DOI] [PubMed] [PMC]

19.

Waarts MR, Stonestrom AJ, Park YC, Levine RL. Targeting mutations in cancer. J Clin Invest. 2022;132:e154943. [DOI] [PubMed] [PMC]

20.

Persi E, Sudalagunta PR, Wolf YI, Canevarolo RR, Damaghi M, Shain KH, et al. Genome-level selection in tumors as a universal marker of resistance to therapy. Nat Commun. 2025;16:6535. [DOI] [PubMed] [PMC]

21.

Liu B, Zhou H, Tan L, Siu KTH, Guan XY. Exploring treatment options in cancer: Tumor treatment strategies. Signal Transduct Target Ther. 2024;9:175. [DOI] [PubMed] [PMC]

22.

Esmaeilpour D, Zare EN, Hassanpur M, Sher F, Sillanpää M. Comparative examination of the chemistry and biology of AI-driven gold NPs in Theranostics: New insights into biosensing, bioimaging, genomics, diagnostics, and therapy. Nanomedicine. 2025;67:102821. [DOI] [PubMed]

23.

Wolfsberg E, Paul JS, Tycko J, Chen B, Bassik MC, Bintu L, et al. Machine-guided dual-objective protein engineering for deimmunization and therapeutic functions. Cell Syst. 2025;16:101299. [DOI] [PubMed] [PMC]

24.

Di Cerbo V, Song HW, Herbst L, Hart SJ, Ladi R, Jiang S, et al. Artificial intelligence, machine learning, and digitalization systems in the cell and gene therapy sector: a guidance document from the ISCT industry committees. Cytotherapy. 2025;27:903–9. [DOI] [PubMed]

25.

Approved Cellular and Gene Therapy Products [Internet]. [cited 2025 Jul 1]. Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products

26.

Tu Z, Chen Y, Zhang Z, Meng W, Li L. Barriers and solutions for CAR-T therapy in solid tumors. Cancer Gene Ther. 2025;[Epub ahead of print]. [DOI] [PubMed]

27.

Ginn SL, Mandwie M, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2023-an update. J Gene Med. 2024;26:e3721. [DOI] [PubMed]

28.

Stevens D, Claborn MK, Gildon BL, Kessler TL, Walker C. Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy. Ann Pharmacother. 2020;54:1001–9. [DOI] [PubMed]

29.

Seker Yilmaz B, Gissen P. Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency. Biomedicines. 2023;11:2227. [DOI] [PubMed] [PMC]

30.

First patient treated with groundbreaking gene therapy trial [Internet]. Great Ormond Street Hospital for Children; c2025 [cited 2025 Jul 22]. Available from: https://www.gosh.nhs.uk/news/first-patient-treated-with-groundbreaking-gene-therapy-trial/

31.

FDA Investigating Deaths Due to Acute Liver Failure Following Treatment with Sarepta’s AAVrh74 Gene Therapies [Internet]. [cited 2025 Jul 22]. Available from: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-deaths-due-acute-liver-failure-following-treatment-sareptas-aavrh74-gene-therapies

32.

Raposo VL. The First Chinese Edited Babies: A Leap of Faith in Science. JBRA Assist Reprod. 2019;23:197–9. [DOI] [PubMed] [PMC]

33.

Wang H, Yang H. Gene-edited babies: What went wrong and what could go wrong. PLoS Biol. 2019;17:e3000224. [DOI] [PubMed] [PMC]

34.

Ma Y, Zhang L, Qin C. The first genetically gene-edited babies: It's “irresponsible and too early”. Animal Model Exp Med. 2019;2:1–4. [DOI] [PubMed] [PMC]

35.

Rueda J, de Miguel Beriain Í, Montoliu L. Affordable Pricing of CRISPR Treatments is a Pressing Ethical Imperative. CRISPR J. 2024;7:220–6. [DOI] [PubMed]

36.

National Academies of Sciences, Engineering, and Medicine; National Academy of Medicine; National Academy of Sciences; Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations. Human Genome Editing: Science, Ethics, and Governance. Washington (DC): National Academies Press (US); 2017.

37.

Human Gene Therapy Products Incorporating Human Genome Editing [Internet]. [cited 2025 Jul 1]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-products-incorporating-human-genome-editing

38.

Knoppers BM, Kleiderman E. “CRISPR babies”: What does this mean for science and Canada? CMAJ. 2019;191:E91–2. [DOI] [PubMed] [PMC]

39.

Kliegman M, Zaghlula M, Abrahamson S, Esensten JH, Wilson RC, Urnov FD, et al. A roadmap for affordable genetic medicines. Nature. 2024;634:307–14. [DOI] [PubMed]

40.

Guo C, Ma X, Gao F, Guo Y. Off-target effects in CRISPR/Cas9 gene editing. Front Bioeng Biotechnol. 2023;11:1143157. [DOI] [PubMed] [PMC]

41.

Aljabali AAA, El-Tanani, Tambuwala MM. Principles of CRISPR-Cas9 technology: Advancements in genome editing and emerging trends in drug delivery. J Drug Del Sci Tech. 2024;92:105338. [DOI]

42.

Kim NG, Aubert M, Haick AK, Massa PA, Loprieno MA, Walter M, et al. Minimization of gene editing off-target effects by tissue restriction of expression. BioRxiv [Preprint]. Available from: https://www.biorxiv.org/content/10.1101/2025.01.21.634017v1.full.pdf

43.

Merlin JPJ, Abrahamse H. Optimizing CRISPR/Cas9 precision: Mitigating off-target effects for safe integration with photodynamic and stem cell therapies in cancer treatment. Biomed Pharmacother. 2024;180:117516. [DOI] [PubMed]

44.

Lopes R, Prasad MK. Beyond the promise: evaluating and mitigating off-target effects in CRISPR gene editing for safer therapeutics. Front Bioeng Biotechnol. 2024;11:1339189. [DOI] [PubMed] [PMC]

45.

Soula A, Leseigneur F, Anwar A, Ozdoganoglu B, Gurung J, Bhatti H, et al. The manufacture of AAV for gene therapy applications using a closed, semi-automated hollow-fiber bioreactor. Mol Ther Methods Clin Dev. 2025;33:101496. [DOI] [PubMed] [PMC]

46.

Drago D, Foss-Campbell B, Wonnacott K, Barrett D, Ndu A. Global regulatory progress in delivering on the promise of gene therapies for unmet medical needs. Mol Ther Methods Clin Dev. 2021;21:524–9. [DOI] [PubMed] [PMC]

47.

Ossandon H, Armijo N, Vargas C, Repetto GM, Espinoza MA. Challenges for gene therapy in the financial sustainability of health systems: a scoping review. Orphanet J Rare Dis. 2024;19:243. [DOI] [PubMed] [PMC]

48.

Zhang J, Chen L, Zhang J, Wang Y. Drug Inducible CRISPR/Cas Systems. Comput Struct Biotechnol J. 2019;17:1171–7. [DOI] [PubMed] [PMC]

49.

Chen H, Li N, Cai Y, Ma C, Ye Y, Shi X, et al. Exosomes in neurodegenerative diseases: Therapeutic potential and modification methods. Neural Regen Res. 2026;21:478–90. [DOI] [PubMed] [PMC]

50.

Chehelgerdi M, Chehelgerdi M, Allela OQB, Pecho RDC, Jayasankar N, Rao DP, et al. Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation. Mol Cancer. 2023;22:169. [DOI] [PubMed] [PMC]

51.

Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther. 2024;9:78. [DOI] [PubMed] [PMC]

52.

Hunt TD. Will Advances in Genetic Medicine Lessen the Need for Germline Modifications? CRISPR J. 2025;[Epub ahead of print]. [DOI] [PubMed]

53.

Verma M, Ozer I, Xie W, Gallagher R, Teixeira A, Choy M. The landscape for lipid-nanoparticle-based genomic medicines. Nat Rev Drug Discov. 2023;22:349–50. [DOI] [PubMed]

54.

Chen C, Wang J, Pan D, Wang X, Xu Y, Yan J, et al. Applications of multi-omics analysis in human diseases. MedComm (2020). 2023;4:e315. [DOI] [PubMed] [PMC]

55.

Mai J, Lu M, Gao Q, Zeng J, Xiao J. Transcriptome-wide association studies: recent advances in methods, applications and available databases. Commun Biol. 2023;6:899. [DOI] [PubMed] [PMC]

56.

Quality, preclinical and clinical aspects of gene therapy medicinal products - Scientific guideline [Internet]. European Medicines Agency; c1995-2025 [cited 2025 Jul 22]. Available from: https://www.ema.europa.eu/en/quality-preclinical-clinical-aspects-gene-therapy-medicinal-products-scientific-guideline#current-effective-version-8392

57.

Cellular & Gene Therapy Guidances [Internet]. [cited 2025 Jul 22]. Available from: https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances

58.

Lu J, Xu L, Wei W, He W. Advanced therapy medicinal products in China: Regulation and development. MedComm (2020). 2023;4:e251. [DOI] [PubMed] [PMC]

59.

Owusu Ansah E. Ethical Challenges and Controversies in the Practice and Advancement of Gene Therapy. Adv Cell Gen Ther. 2022;2022:1015996. [DOI]

60.

Joseph AM, Karas M, Ramadan Y, Joubran E, Jacobs RJ. Ethical Perspectives of Therapeutic Human Genome Editing From Multiple and Diverse Viewpoints: A Scoping Review. Cureus. 2022;14:e31927. [DOI] [PubMed] [PMC]

61.

Li Y, Tenchov R, Smoot J, Liu C, Watkins S, Zhou Q. A Comprehensive Review of the Global Efforts on COVID-19 Vaccine Development. ACS Cent Sci. 2021;7:512–33. [DOI] [PubMed] [PMC]

62.

Miteu GD. Ethics in scientific research: a lens into its importance, history, and future. Ann Med Surg (Lond). 2024;86:2395–8. [DOI] [PubMed] [PMC]

63.

Kandlbinder A, Peter-Spiess MH, Leeners B, Mollaysa A, Cavazza T, Meier A, et al. Strategies for Interdisciplinary Human Gene Editing Research: Insights from a Swiss Project. CRISPR J. 2025;8:79–88. [DOI] [PubMed] [PMC]